Pharmaceutical compositions comprising 1-isopropyl-3-[ (4-M-toluidino-3-pyridyl) sulphonyl] -urea as active ingredient

ABSTRACT

The present invention concerns the use of 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea in the pharmaceutical field. In particular, it proposes the use of a pure and stable polymorphic form of 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea for the preparation of solid pharmaceutical forms, and likewise a method of synthesis to obtain such a pure and stable polymorphic form of 1-isopropyl-3-[(4-m-toluidino-3-pyridiyl)sulphonyl]-urea.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Italian Patent Application No. MI2002A000639, filed Mar. 27, 2002, and is hereby incorporated by reference to the extent permitted by law.

FIELD OF THE INVENTION

The present invention concerns pharmaceutical compositions comprising 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea as active ingredient.

BACKGROUND OF INVENTION

Torsemide (or torasemide), namely 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea or N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-3-pyridinesulphonamide, or 3-isopropylcarbamylsulphonamide-4-(3′-methylphenyl)aminopyridine, C₁₆H₂₀N₄O₃S, m.w. 348.43, CAS Nr.56211-40-6, described for the first time in example 71 of the West German Patent DE 25 16 025 dating from 1974, is a compound which has well known applicability in the pharmaceutical field, in particular for the manufacture of diuretic agents. Recently, torsemide has also been proposed for the treatment of cerebral edema (U.S. Pat. No. 5,486,530).

Like many molecules of organic nature, also torsemide shows the phenomenon of polymorphism (the existence of various crystalline modifications) in the solid state, which makes the preparation of solid pharmaceutical forms of it particularly problematic. As is well known to experts in the art, polymorphic forms of a compound demonstrate, by means of their different crystalline structure, distinct physico-chemical characteristics (amongst which not only thermodynamic stability, but also the kinetic characteristics), amongst which, purely by means of example, solubility, with obvious respective consequences on the resulting pharmacokinetics. It can thus occur that some polymorphic forms of a given compound are particularly suited to the preparation of specific solid pharmaceutical formulations with defined characteristics, for example bioavailability in patients, whilst other polymorphic forms instead require completely different formulations or are even unusable. Despite the fact that, clearly, every polymorphic form is characterised by its thermodynamic stability which distinguishes it from the others, the synthesis reactions and the purification treatments used in industry in practice always take place under kinetically controlled conditions, frequently favouring the formation, at least partially, of metastable polymorphic forms. For the expert in the art wishing to formulate pharmaceutical compositions with highly reproducible pharmacokinetics, it is therefore critical not only to understand the single polymorphs of a compound but also their formation conditions in the different synthesis reactions and in the various contemplatable purification methods, because certain polymorphs or mixtures of various polymorphs are frequently poorly suited or poorly usable to its ends. Scrupulous study of the conditions of formation of the various polymorphic forms is also necessary with reference to the storage of the raw materials, in that, according to the relative metastability and following unpredictable interactions, transformations between various polymorphs are also possible downstream of the procedures primarily applied to the attainment of the active ingredient in pure form.

Consequently, following the discovery of the polymorphy of torsemide, numerous and great efforts have been invested by various groups of researchers to explore its single polymorphic forms, the usability of these polymorphic forms in the pharmaceutical field and, last but not least, the conditions which lead to the formation of certain polymorphic forms in certain environments.

For example, in the American Patents re-issue 34,672 and re-issue 34,580, which date from 1985, are described a form I and a form II of torsemide characterised amongst others, respectively, by a melting point interval between approx. 159° C. and approx 161.5° C. for form I and a melting point interval of between approx. 157.5° C. and approx. 160° C. for form II. In particular, a method for the attainment of form I of torsemide in pure form, suitable for the production of solid pharmaceutical forms is also described.

Further verifications have been carried out, independently, in 1994, by a group of Japanese researchers which in the context of a “review” appearing in a scientific magazine (“Chemical structure and physico-chemical properties of torasemide”, Kondo et al. Iyakuhin Kenkyu, Vol. 25, No. 9 (1994)) have carried out very deep physico-chemical studies and have acquired very detailed analytical data on samples of torsemide. New methods of synthesis for various forms of torsemide have also been proposed, then characterised in a very complete manner within the scope of this study. The polymorphic form II of torsemide described in this work is obtained from crude torsemide which is dissolved according to well defined proportions (1:16) in water which is then alkalinised with aqueous solutions of sodium hydroxide until reaching a pH of 10. Later, the pH is lowered by the addition of acetic acid until neutralised (pH 7), and the crystals thus obtained are filtered. In addition, it has been found that it is possible to obtain a pure form I of torsemide from this form II by the resuspension of the crystals of form II in a defined quantity of water with subsequent agitation over 20 days at room temperature. With the objective of exploration of the applicability of the various forms of torsemide for the manufacture of pharmaceutical products, the authors of this article have also explored the relative stability of the polymorphic form I and form II obtained according to their method. Whilst form I has been judged sufficiently stable, form II has instead been held to be poorly stable because it is susceptible to humidity, in that it (auto)-transforms into form I in the presence of just water. As a consequence, it has been concluded by Kondo et al. that form II of torsemide obtained and studied by them is not suitable for the preparation of solid pharmaceutical forms.

Over the following years, various groups have then independently identified further polymorphic forms of torsemide, and have studied the characteristics let alone the conditions for their attainment and they have also proposed them validly usable as active ingredients in the preparation of pharmaceutical compositions. Despite all this work, in part also very recently, and despite the notable amount of data recorded and studies completed, the only polymorphic form of torsemide actually used in the pharmaceutical field up to now in the form of solid administrations, is the form I of torsemide, specifically that described in the American Patent Reissue 34,580 and Reissue 34,672.

In fact, up until a short time ago, torsemide was not quoted in any Pharmacopoeia in the world. Torsemide is entered in the US Pharmacopoeia only in the ambit of the edition published in 2001 (USP25) and valid from January 2002 onwards, whilst the only official specification available up to then which provided instructions on the characteristics of torsemide for use as an active ingredient in pharmaceutical preparations was a monograph published during the Pharmacopeial Forum 26, No. 3, then updated ad Pharmacopeial Forum 26, No. 5. It is important to note that in USP 25 and in the preceding monographs, reference is made exclusively to form I of torsemide, but the relative reference standard, was not and is still not available in that it is still missing from the official catalogue of the “USP and FCC Reference Standards and USP Authentic Substances”, including the November-December 2001 edition. The availability of the standard does not even appear in the 1^(st) Supplement to the USP which will be official from the 1^(st) of April 2002.

From the above, it is clear that 27 years after the discovery of torsemide, and despite the considerable amount of additional polymorphic forms described, the only polymorphic form effectively used in the pharmaceutical field for the preparation of solid formulations is the form I of torsemide as it is described in the American Patent Reissue 34,580 and Reissue 34,672.

On the other hand, it is known however that the solubility of form I is not optimal with respect to that of the other polymorphs, which is reflected amongst others also in the pharmacokinetic characteristics of the respective solid pharmaceutical forms containing form I of torsemide, and therefore the availability of new pharmaceutical forms which contain other polymorphs of torsemide which show greater solubility is highly desirable. The satisfaction of such an objective is the subject of the present invention.

SUMMARY OF INVENTION

To overcome the problems of the known art, and in particular to obtain solid pharmaceutical forms of torsemide containing an active ingredient characterised by very high solubility, according to a first aspect, the present invention proposes the use of pure and stable form II of torsemide for the preparation of solid pharmaceutical forms. Thus doing, one obtains new solid pharmaceutical compositions containing form II of 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea as active ingredient.

A further aspect of the present invention is the availability of a procedure which guarantees making available pure and stable form II of torsemide as above from crude torsemide with high yield and with very high reproducibility.

A further aspect of the present invention is the provision of an analytical method able to determine whether a given preparation of torsemide form II is pure and stable.

DESCRIPTION OF THE FIGURES

The invention, as described in the ambit of the present patent application is further illustrated by the following Figures in which, in the following descriptions of the graphical representations, the “Y” axis is intended as the vertical axis of the graph and the “X” axis is intended as the horizontal axis of the graph:

FIG. 1: X-ray diffractogram of powders of form II of torsemide as published by Kondo et al. in Iyakuhin Kenkyu Vol. 25 No. 9 (1994). On the Y axis is represented intensity, whilst the X axis reports the angle of reflection (in degrees 2 theta), decreasing from left to right.

FIG. 2: FT-IR spectra of form II and form I of torsemide as published by Kondo et al. in Iyakuhin Kenkyu Vol. 25 No. 9 (1994). On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 3: X-ray diffractogram of powders of form II of torsemide as obtainable through the process of the present invention. On the Y axis is represented the intensity (counts), whilst the X axis reports the angle of reflection (in degrees 2 theta) increasing from left to right.

FIG. 4: FT-IR spectrum (Jasco) of form II of torsemide as obtainable by the process of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 5: FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 6: Enlargement (4000-2000 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable trough the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 7: Enlargement (1758.6-1391.0 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 8: Enlargement (1750-1600 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 9: Enlargement (1991.8-1198.9 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 10: Enlargement (1198.9-441.8 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 11: X-ray diffractogram of powders of form I of torsemide as published by Kondo et al. in Iyakuhin Kenkyu Vol. 25 No. 9 (1994). On the Y axis is represented the intensity, whilst the X axis reports the angle of reflection (in degrees 2 theta) decreasing from left to right.

FIG. 12: X-ray diffractogram of powders of form I of torsemide used by the inventors of the present patent application. On the Y axis is represented the intensity (counts), whilst the X axis reports the angle of reflection (in degrees 2 theta) increasing from left to right.

FIG. 13: FT-IR spectrum (Jasco) of form I of torsemide used by the inventors of the present patent application. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 14: FT-IR spectrum (Perkin Elmer) of form I of torsemide used by the inventors of the present patent application. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 15: Enlargement (4000-1991.8 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form I of torsemide used by the inventors of the present patent application. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 16: Enlargement (2000-1198.9 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form I of torsemide used by the inventors of the present patent application. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 17: Enlargement (1196.2-433.5 cm⁻¹) of the FT-IR spectrum (Perkin Elmer) of form I of torsemide used by the inventors of the present patent application. On the Y is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 18: X-ray diffractogram of powders of form II of torsemide as obtainable through the procedure of the present invention with the addition of 2% (by weight) of form I of torsemide. On the Y axis is represented the intensity (counts), whilst the X axis reports the angle of reflection (in degrees 2 theta) increasing from left to right.

FIG. 19: X-ray diffractogram of powders of form II of torsemide as obtainable through the procedure of the present invention with the addition of 4% (by weight) of form I of torsemide. On the Y axis is represented the intensity (counts), whilst the X axis reports the angle of reflection (in degrees 2 theta) increasing from left to right.

FIG. 20: X-ray diffractogram of powders of form II of torsemide as obtainable through the procedure of the present invention with the addition of 8% (by weight) of form I of torsemide. On the Y axis is represented the intensity (counts), whilst the X axis reports the angle of reflection (in degrees 2 theta) increasing from left to right.

FIG. 21: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as obtainable through the procedure of the present invention. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 22: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as available through the procedure of the present invention with the addition of 1% (by weight) of form I. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 23: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as obtainable through the procedure of the present invention with the addition of 3% (by weight) of form I of torsemide. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 24: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as obtainable through the procedure of the present invention with the addition of 5% (by weight) of form I of torsemide. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 25: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as obtainable through the procedure of the present invention with the addition of 10% (by weight) of torsemide form I. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 26: FT-IR spectrum (Jasco) enlarged between 2000 and 1400 cm⁻¹ of form II of torsemide as obtainable through the procedure of the present invention with the addition (for comparison) of 1%, 3%, 5% and 10% (by weight) of torsemide form I. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 27: FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure in the present invention with the addition of 1% (by weight) of form I of torsemide. On the Y axis is represented the transmittance (in %), whilst the X axis reports the wave number (in cm⁻¹).

FIG. 28: FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtainable through the procedure of the present invention with the addition of 4% (by weight) of form I of torsemide. On the Y axis is represented the transmittance (in %), whilst the X axis reports the number of waves (in cm⁻¹).

DETAILED DESCRIPTION OF THE INVENTION

Within the ambit of the present invention, it has been surprisingly found that pure form II of torsemide, as described and characterised in the works by Kondo et al., is also stable over long-term storage and under conditions of high humidity, which render it suitable for the preparation of solid pharmaceutical forms which derive the advantage of the increased solubility of form II of torsemide. Such a finding is unexpected, in that Kondo et al. had instead concluded that form II of torsemide auto-transformed itself into form I in the presence of humidity, with the consequence that the attainment of a stable form II over time, at least under realistically operable storage conditions with reasonable economic efforts in the distribution of active ingredients and pharmaceutical products, had been judged virtually impossible. In fact, on the basis of the considerations made by Kondo et al., one concludes that form II, with passing time, would have remained at least partially “contaminated” by form I, at least if the production and the distribution of form II of torsemide, let alone the preparation of solid pharmaceutical forms obtainable from it and their distribution and their storage (both by the reseller, and by the patient such as the “end consumer”), had not taken place under strictly anhydrous conditions.

The inventors of the present patent application have found however that form II of torsemide, as it was already characterised in a more general manner in Kondo et al., and in particular in its pure and stable form, for example obtainable through the procedure described in the present patent application, is instead satisfactorily inert during long periods of storage, even in conditions of high humidity. Consequently form II of torsemide is not susceptible (under usual storage conditions) to auto-transformation into form I and therefore form II is suitable for the preparation of solid pharmaceutical forms. In addition, the inventors of the present invention have also perfected a new particularly preferred method of synthesis which produces pure and stable form II of torsemide, suitable for the preparation of solid pharmaceutical forms with high yields and optimum reproducibility. In particular, according to the method of synthesis found by the inventors of the present patent application, one obtains very high yields of pure and stable form II of torsemide, namely 96% or greater with respect to crude torsemide. In order to study in detail the characteristics of forms I and II of torsemide and of their reciprocal transformations, and in the absence of standard samples and/or “official” data (not available from the USP), form I and form II discussed in the present patent application have been identified with reference to the above mentioned article by Kondo et al. (“Chemical structure and physico-chemical properties of torasemide”, Kondo et al. Iyakuhin Kenkyu, Vol 25, No. 9 (1994) in which are published the X-ray diffractograms of powders of form II of torsemide (FIG. 1) and of form I of torsemide (FIG. 11) registered on a Siemens D500 powder diffractometer, as well as the relative FT-IR spectra—registered on a Perkin Elmer 320 spectrophotometer—of both polymorphic forms (FIG. 2).

The inventors of the present patent application have obtained form I and form II of torsemide from crude torsemide by following the general strategy proposed by Kondo et al. and have studied in detail the differences which appear between form I and form II of torsemide in the respective X-ray diffractograms (registered on a PW 1700 diffractometer) and also in the FT-IR spectra registered in KBr (with FT-IR apparatus obtainable from Jasco and from Perkin Elmer) and have found that, in particular through the analysis of the relative FT-IR spectra in KBr it is possible to still observe contaminations of 1% (by weight) of form I of torsemide in a sample composed of form II of torsemide. The applicability and universality of such a method of detection of small quantities of form I of torsemide in a sample of form II of torsemide which is based on the evaluation of the presence or absence of a peak at approx. 1697 cm⁻¹, characteristic of the FT-IR spectra of form I of torsemide, has been verified on two FT-IR spectrophotometers supplied by different manufacturers (Perkin Elmer and Jasco). It has thus been found that the detection method which is based on such an evaluation of the FT-IR spectrum in KBr is markedly more sensitive than the evaluation of the relative X-ray diffractograms of the powders, in that the detection limits of small amounts of form I of torsemide in a sample of form II of torsemide, in particular on the basis of the presence or absence of a signal at approx. 5.7° two theta present exclusively in the -ray diffractogram of the powders of form I of torsemide (see FIGS. 11 and 12) is only 2% (by weight). Consequently, with the method of detection of very small contaminations of form I of torsemide in a sample of form II of torsemide which is based on the evaluation of the presence of a peak at approx. 1697 cm⁻¹ in the FT-IR spectrum, used and described in the present patent application request, the inventors have studied and perfected, for the first time, an analytical means of greater sensitivity, also then used for the verification of the progress of the stability tests according to the ICH (Q1A, “Stability testing of new Drug Substances and new Drug Products”, 1^(st) edition Oct. 27, 1997 and 2^(nd) edition Nov. 8, 2000) to which have been subjected 3 samples of pure form II of torsemide, to allow the observation of even minimal variations of the polymorphic composition of a sample over time.

It has in fact been surprisingly found that—contrary to what taught by Kondo et al.—form II of torsemide (as previously characterised by Kondo through the X-ray diffractograms of the powders of FIG. 1 and through the FT-IR spectra of FIG. 2), and more preferably the pure and stable form II of torsemide obtainable through the procedure described in the present patent application, is quite stable under normal storage conditions (non anhydrous) in the treatment of products in the pharmaceutical industry and in the distribution of medicines to allow the preparation of solid pharmaceutical forms, in that—within the limits of detection—it does not undergo any transformation into form I of torsemide. Consequently, the present invention makes available, for the first time, solid pharmaceutical compositions comprising form II of torsemide as active ingredient.

Within the ambit of the present invention, “pure” form II of torsemide is intended as a form II of torsemide which according to the analysis of the FT-IR spectra registered in KBr contains less than 1% (by weight) of form I of torsemide.

Within the ambit of the present invention, “stable” form II of torsemide is intended as a pure form II which does not show detectable polymorphic transformations after 6 months of accelerated testing (at 40°±2° C./75±5% of relative humidity) as by the ICH (Q1A, “Stability testing of new Drug Substances and new Drug Products”, 1^(st) edition October 27, 1997 and 2^(nd) edition Nov. 8, 2000). For detectable polymorphic transformations is intended transformations visible from changes of the FT-IR spectrum of form II of torsemide registered in KBr. Specifically, the formation of a contamination of 1% or greater (by weight) of form I of torsemide in a sample of pure form II of torsemide would be a detectable polymorphic transformation by means of the relative change of the FT-IR spectrum registered in KBr which would imply the appearance of a peak in the position at 1697 cm⁻¹.

More precisely, pure and stable form II of torsemide is characterised through the following signals in the X-ray diffractogram of the powders expressing degrees 2 theta: 9.0±0.1; 9.2±0.1; 10.7±0.1; 15.9±0.1; 18.2±0.1; 18.5±0.1; 18.8±0.1; 20.4±0.1; 22.6±0.1; 23.1±0.1; 23.5±0.1. Still more precisely, pure and stable form II of torsemide is characterised through the additional peaks in the X-ray diffractogram reported in table 2. Still more precisely, pure and stable form II of torsemide is characterised through the X-ray diffractogram of the powders of FIG. 3. Still more precisely, pure and stable form II of torsemide is characterised through the following peaks in the FT-IR spectrum registered in KBr: 3354±2 cm⁻¹; 3326±2 cm⁻¹; 3085±2 cm⁻¹; 2964±2 cm⁻¹; 1617±2 cm⁻¹; 1555±2 cm⁻¹; 1510±2 cm⁻¹; 1357±2 cm⁻; 1326±2 cm⁻¹; 1277±2 cm⁻¹; 1234±2 cm⁻¹; 1151±2 cm⁻; 900±2 cm⁻¹; 837±2 cm⁻¹. Still more precisely, pure and stable form II of torsemide is characterised through the peaks in the FT-IR spectrum reported in table 4. Still more precisely, pure and stable form II of torsemide is characterised through the FT-IR spectra in KBr of FIG. 4 or 5.

Still more precisely, pure and stable form II of torsemide is characterised by a melting point in the interval between 159.9° C. and 160.2° C. (measured with a Büchi B-540 instrument).

As mentioned above, form II of torsemide the subject of the present invention is the form II of torsemide as characterised by Kondo et al. and consequently, it can be obtained through any procedure useful for the attainment of form II of torsemide (as characterised by Kondo et al.), naturally on the condition that the form II of torsemide thus obtained be pure and stable within the meaning of the present patent application (namely that the form II of torsemide effectively obtained does not contain detectable contaminations—greater than 1% by weight—of form I). With that aim, the procedure found by the inventors within the ambit of the present invention is particularly advantageous and preferred. In particular, pure and stable form II of torsemide is obtainable with high yield through the process perfected by the inventors of the present patent application and comprising the following steps:

-   -   suspension of crude, dried torsemide in 10 parts (by weight) of         deionised water,     -   the addition of a solution of 48% potassium hydrate, slowly with         stirring, maintaining the temperature at 20-25° C., until         achieving complete solution and without exceeding pH 12.5,     -   filtration of the solution thus obtained through 40 micron paper         filters,     -   gradual acidification of the filtrate thus obtained with         stirring with 80% acetic acid preferably until reaching a pH of         5.3-5.7 maintaining the temperature at 20-25° C. during the         addition, obtaining a suspension,     -   stirring of the suspension for 30 minutes at a temperature of         20-25° C., filtration by suction and washing the solid obtained         with water,     -   drying of the solid in a dryer under vacuum at a temperature of         50° C.

Within the ambit of the present invention, as crude torsemide, is intended any torsemide obtainable through any suitable procedure described in the literature, leaving aside its crystalline form.

As initially said, it has been unexpectedly found that pure and stable form II of torsemide, as obtainable for example through the procedure of the present invention, does not require storage under strictly anhydrous conditions.

Whilst it has been confirmed that pure and stable form II of torsemide transforms into form I if suspended in water and if then subjected to strong heating or if suspended in water and subjected to prolonged treatment, it has instead been found that the pure and stable form of torsemide is not susceptible to transformation into form I under standard storage conditions, even in the presence of considerable relative humidity (75%±5%), in particular under the conditions envisaged by the “ICH” international standard (Q1A, “Stability testing of new Drug Substances and new Drug Products”, 1^(st) edition Oct. 27, 1997 and 2^(nd) edition Nov. 8, 2000) and recognised on the world scale for the evaluation of the stability of pharmaceutical substances.

It is thus found that the pure form II of torsemide as had already been described and characterised by Kondo et al. and preferably as obtainable through the methods of the present invention is not susceptible to humidity during usual storage conditions and consequently, form II of torsemide is indicated for the preparation of solid pharmaceutical formulations which could take advantage of greater solubility of form II (with respect to form I) of torsemide.

Consequently, the present invention proposes, for the first time, solid pharmaceutical compositions comprising form II of 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulphonyl]-urea as active ingredient.

EXPERIMENTAL SECTION Example 1 Synthesis of Form II of Torsemide

One of the chemical synthesis usable to obtain a preparation of crude torsemide is for example the chemical synthesis of torsemide used by Kondo at al., in particular according to FIG. 2 by Kondo. Torsemide thus obtained, following the elimination of the acetone, following the addition of water and following precipitation of the torsemide from the remaining aqueous phase through the addition of acetic acid (until reaching a pH of 5.5) and following washing with deionised water can be used as “crude” torsemide, as defined within the ambit of the present patent application. 49 g of crude, dried torsemide (m.w.=348.43, 0.140 mol) are resuspended in 490 cc of deionised water. Later, 16.5 g of 48% potassium hydrate (m.w.=56.1; 0.141 mol) is slowly added, maintaining the temperature at 20-25° C., until the attainment of complete solution and without exceeding pH 12.5 (pH 12.35 has been reached). The solution is then filtered through 40 micron filter paper.

One then proceeds to the acidification of the filtered solution, to pH 5.3-5.7, by the gradual addition of 11.5 g of 80% acetic acid (m.w.=60.05; 0.153 mol), maintaining the temperature at 20-25° C. during the addition. After having stirred the suspension for 30 minutes at a temperature of 20-25° C., it is filtered by suction, washing the product filter bed with water. The product thus obtainable is then dried in a dryer under vacuum at a temperature of 50° C., finally yielding 47 g of pure torsemide form II (yield, with respect to crude torsemide=96%).

The melting point of the pure form II of torsemide used by the inventors of the present patent application measured with a Büchi B-540 according to USP class 1a (temperature increments of 1° C.±0.5° C./min starting from 10° C. from the expected melting point, inserting the sample at 5° C. from the melting point, then 1° C.±0.5° C./min until reaching the melting point) is 159.9°-160.2° C.

The X-ray diffractogram of the powders of form II of torsemide used by the inventors of the present patent application with a PW 1700 diffractometer (radiation source Cu α1 and a 2 (λ=1.54051 Angstrom and λ=1.54430 Angstrom) is represented in FIG. 3.

The measurement conditions of the diffractogram of FIG. 3 are summarised in table 1, whilst the details of the diffractogram of FIG. 3 are reported in table 2: TABLE 1 Sample identification: TORSEMIDE II diffractometer type: PW1710 BASED Tube Anode: Cu Generator tension [kV]: 40 generator current [mA]: 40 Wavelength alpha1 [Å]: 1.54051 Wavelength alpha 2 [Å]: 1.54439 Intensity ratio (alpha 2/alpha 1): 0.500 Divergence slit: 1° Receiving slit: 0.1 Monochromator used: YES Start angle [°2θ]: 3.000 End angle [°2θ]: 30.000 Step size [°2θ]: 0.010 Maximum intensity: 3433.960 Time per step [s]: 0.7000 Type of scan: STEP Minimum peak tip width: 0.00 Maximum peak tip width: 1.00 Peak base width: 2.00 Minimum significance: 0.75 Number of peaks: 46

TABLE 2 Peak Base Relative Angle Value d Value d Peak width intensity intensity intensity [°2θ] α1 [Å] α2 [Å] [°2θ] [counts] [counts] [%] Significance 3.300 26.7506 26.8180 0.160 71 71 2.1 0.77 6.990 12.6351 12.6669 0.160 88 58 2.6 5.24 7.680 11.5014 11.5304 0.160 121 58 3.5 7.04 8.995 9.8227 9.8475 0.030 1632 58 47.5 0.77 9.210 9.5939 9.6181 0.060 2116 58 61.6 3.29 9.265 9.5371 9.5611 0.040 1673 58 48.7 0.83 10.170 8.6903 8.7122 0.180 773 58 22.5 13.17 10.645 8.3036 8.3245 0.170 3434 58 100.0 53.08 11.530 7.6682 7.6875 0.060 361 58 10.5 1.81 12.060 7.3323 7.3508 0.060 266 58 7.7 1.34 13.485 6.5605 6.5771 0.160 190 58 5.5 8.88 14.255 6.2078 6.2235 0.120 48 58 1.4 1.41 14.845 5.9624 5.9774 0.160 34 58 1.0 1.52 15.420 5.7414 5.7558 0.100 119 58 3.5 1.10 15.870 5.5796 5.5936 0.050 795 58 23.2 0.80 15.925 5.5604 5.5744 0.060 686 58 20.0 1.56 16.375 5.4086 5.4222 0.080 449 58 13.1 2.57 17.300 5.1214 5.1343 0.180 231 58 6.7 9.53 18.200 4.8702 4.8824 0.160 471 58 13.7 8.78 18.530 4.7842 4.7962 0.080 936 58 27.3 3.45 18.840 4.7061 4.7180 0.080 1156 58 33.7 3.84 19.325 4.5891 4.6007 0.160 380 58 11.1 6.64 19.875 4.4633 4.4746 0.100 376 58 11.0 1.25 20.125 4.4085 4.4196 0.100 686 58 20.0 2.08 20.410 4.3475 4.3585 0.060 2116 58 61.6 2.51 20.465 4.3360 4.3469 0.030 1764 58 51.4 0.94 20.855 4.2558 4.2665 0.030 441 58 12.8 1.24 21.195 4.1883 4.1988 0.140 493 58 14.4 7.08 21.765 4.0798 4.0901 0.140 480 58 14.0 8.57 22.155 4.0089 4.0190 0.140 240 58 7.0 3.12 22.555 3.9387 3.9486 0.070 1129 58 32.9 2.93 23.105 3.8462 3.8559 0.200 734 58 21.4 12.91 23.475 3.7864 3.7959 0.180 936 58 27.3 18.52 24.055 3.6964 3.7057 0.100 202 58 5.9 0.86 24.560 3.6215 3.6306 0.070 655 58 19.1 2.14 25.020 3.5560 3.5649 0.120 404 58 11.8 4.08 25.225 3.5275 3.5364 0.120 279 58 8.1 1.21 25.525 3.4867 3.4955 0.180 213 58 6.2 5.49 26.125 3.4080 3.4166 0.160 219 58 6.4 5.46 26.985 3.3013 3.3096 0.160 350 58 10.2 6.50 27.495 3.2412 3.2494 0.100 146 58 4.3 0.76 27.630 3.2257 3.2338 0.060 213 58 6.2 1.24 28.035 3.1800 3.1880 0.220 243 58 7.1 10.23 28.530 3.1259 3.1338 0.070 156 58 4.6 1.49 29.090 3.0670 3.0748 0.180 193 58 5.6 7.62 29.720 3.0034 3.0110 0.160 313 58 9.1 4.63

The FT-IR spectrum, registered in KBr with a Jasco FT-IR 300-E (“diffuse reflectance”) of form II of torsemide used by the inventors of the present patent application is represented in FIG. 4.

The measurement conditions of the FT-IR spectrum of FIG. 4 are summarised in table 3, whilst some details of the spectrum are summarised in table 4. TABLE 3 Accumulation 32 times Resolution 4 cm⁻¹ Apodisation Cosine Sample name Torsemide II Gain 16 Speed 2.0 mm/sec Delay time 0 sec Light source Ni/Cr Filament Detector 1 Beam splitter KBr

TABLE 4 Peak number Peak position [cm⁻¹] Transmittance 1 3678.55 73.9% 2 3440.38 72.6% 3 3354.57 31.5% 4 3325.64 29.2% 5 3085.55 28.5% 6 2964.05 29.0% 7 2352.73 56.9% 8 2053.82 60.0% 9 1694.16 66.4% 10 1643.05 24.9% 11 1616.06 24.9% 12 1555.31 21.0% 13 1511.23 23.0% 14 1455.03 36.0% 15 1356.68 36.9% 16 1325.82 32.7% 17 1276.65 25.0% 18 1234.22 26.8% 19 1151.29 27.1% 20 1078.98 41.0% 21 1041.37 49.7% 22 1001.84 58.0% 23 952.66 56.3% 24 899.63 34.1% 25 836.95 35.8% 26 789.71 44.2% 27 763.67 41.6% 28 727.03 42.6% 29 691.36 48.3% 30 650.86 48.7% 31 609.40 31.1%

The FT-IR spectrum, registered in KBr with a Perkin Elmer FT-IR Spectrum-one (“diffuse reflectance”) of form II of torsemide used by the inventors of the present patent application is represented in FIG. 5. Various enlargements obtained with the Perkin Elmer FT-IR Spectrum-one with which some details of the FT-IR spectrum of torsemide form II used by the inventors of the present invention are better are represented in FIG. 6-10.

Example 2 Synthesis of Form I of Torsemide

Form I of torsemide is obtainable from form II of torsemide as above according to the instructions of Kondo, namely by suspension of an aliquot of form II in water (approx. 23 parts by weight) and subsequent stirring for 20 days at room temperature. The melting point of form I of torsemide, used by the inventors of the present patent application, measured with a Büchi B-540 according to USP class 1a (temperature increments of 1° C.±0.5° C./min starting from 10° C. from the expected melting point, inserting the sample at 5° C. from the melting point, then 1° C.±0.5° C./min until reaching the melting point), is 160.1°-160.5° C.

The X-ray diffractogram of the torsemide form I used by the inventors of the present patent application with a PW 1700 diffractometer (radiation source Cu α1 and α2 (λ=1.54051 Angstrom and λ=1.54430 Angstrom) is represented in FIG. 12.

The measurement conditions of the diffractogram of FIG. 12 are summarised in table 5, whilst the details of the diffractogram of FIG. 16 are reported in table 6: TABLE 5 Sample Identification: TORSEMIDE I diffractometer type: PW1710 BASED Tube Anode: Cu generator tension [kV]: 40 generator current [mA]: 40 Wavelength alpha1 [Å]: 1.54051 Wavelength alpha2 [Å]: 1.54439 Intensity ratio (alpha2/alpha1): 0.500 Divergence slit: 1° Receiving slit: 0.1 Monochromator used: YES Start angle [°2θ]: 3.000 End angle [°2θ]: 30.000 Step size [°2θ]: 0.010 Maximum intensity: 4435.560 Step time per step [s]: 0.7000 Scanning type of scan: STEP Minimum peak tip width: 0.00 Maximum peak tip width: 1.00 Peak base width: 2.00 Minimum significance: 0.75 Number of peaks: 39

TABLE 6 Peak Base Relative Angle Value d Value d Peak width intensity intensity intensity [°2θ] α1 [Å] α2 [Å] [°2θ] [counts] [counts] [%] Significance 3.080 28.6608 28.7330 0.320 96 41 2.2 0.76 3.900 22.6363 22.6934 0.070 69 41 1.6 0.91 5.650 15.6284 15.6678 0.130 3058 41 68.9 33.82 6.840 12.9119 12.9444 0.140 79 41 1.8 1.78 7.505 11.7692 11.7988 0.070 506 41 11.4 2.32 10.080 8.7677 8.7898 0.160 17 41 0.4 1.03 11.415 7.7451 7.7647 0.200 62 41 1.4 3.10 12.025 7.3536 7.3721 0.120 40 41 0.9 1.39 12.695 6.9670 6.9845 0.070 520 41 11.7 1.90 13.060 6.7731 6.7901 0.160 762 41 17.2 8.30 13.310 6.6464 6.6631 0.030 681 41 15.4 0.76 13.470 6.55678 6.5843 0.080 357 41 8.1 0.77 13.710 6.4534 6.4696 0.120 144 41 3.2 1.06 14.105 6.2735 6.2893 0.100 100 41 2.3 1.33 15.010 5.8972 5.9121 0.100 190 41 4.3 2.00 15.720 5.6325 5.6466 0.080 81 41 1.8 0.88 16.440 5.3874 5.4009 0.140 243 41 5.5 3.98 17.240 5.1391 5.1521 0.120 4436 41 100.0 22.70 17.645 5.0221 5.0347 0.070 306 41 6.9 1.39 18.465 4.8009 4.8130 0.260 692 41 15.6 32.51 19.670 4.5094 4.5207 0.160 182 41 4.1 2.25 19.880 4.4622 4.4735 0.080 159 41 3.6 0.97 20.340 4.3623 4.3733 0.120 986 41 22.2 1.10 20.645 4.2986 4.3094 0.040 2162 41 48.7 0.99 20.820 4.2628 4.2736 0.080 858 41 19.4 1.42 21.595 4.1116 4.1219 0.100 210 41 4.7 1.49 22.110 4.0170 4.0271 0.060 365 41 8.2 1.34 22.210 3.9991 4.0092 0.100 471 41 10.6 3.13 22.600 3.9310 3.9409 0.080 296 41 6.7 0.76 23.150 3.8388 3.8485 0.050 1722 41 38.8 0.99 24.405 3.6442 3.6533 0.160 266 41 6.0 6.05 25.235 3.5261 3.5350 0.100 240 41 5.4 1.20 25.665 3.4680 3.4768 0.060 681 41 15.4 1.62 26.355 3.3788 3.3873 0.120 98 41 2.2 1.24 26.770 3.3273 3.3357 0.050 600 41 13.5 0.79 27.725 3.2149 3.2229 0.120 346 41 7.8 2.80 28.235 3.1579 3.1659 0.050 1218 41 27.5 1.30 28.890 3.0878 3.0956 0.180 228 41 5.1 6.10 29.595 3.0158 3.0234 0.160 161 41 3.6 2.95

The FT-IR spectrum, registered in KBr with a Jasco FT-IR 300-E (“diffuse reflectance”) of form I of torsemide used by the inventors of the present patent application is represented in FIG. 13.

The measurement conditions of the FT-IR spectrum of FIG. 13 are summarised in table 7, whilst the details of the spectrum are summarised in table 8. TABLE 7 Accumulation 32 times Resolution 4 cm⁻¹ Apodisation Cosine Sample name Torsemide I Gain 16 Speed 2.0 mm/sec Delay time 0 sec Light source Ni/Cr Filament Detector 1 Beam splitter KBr

TABLE 8 Peak number Peak position Transmittance 1 3350.71 63.6% 2 3280.32 62.8% 3 2976.59 65.5% 4 1697.05 52.5% 5 1633.41 55.5% 6 1590.99 51.2% 7 1515.77 51.7% 8 1403.92 57.9% 9 1359.57 61.5% 10 1263.15 62.5% 11 1237.11 61.8% 12 11.43.58 52.2% 13 1110.80 62.4% 14 1047.16 59.6% 15 900.59 65.9% 16 823.46 62.2% 17 774.28 64.3%

The IR spectrum, registered in KBr with a Perkin Elmer FT-IR Spectrum-one (“diffuse reflectance”) of form I of torsemide used by the inventors of the present patent application is represented in FIG. 14. Various enlargements obtained with the Perkin Elmer FT-IR Spectrum-one from which some details of the FT-IR spectrum of form I of torsemide used by the inventors of the present patent application are better, are represented in FIGS. 15-17.

Example 3 The Detection Limits of Contaminations of Form I in Samples of Form II of Torsemide

To establish the most relevant and suitable analytical method for the detection of small quantities of contaminating form I of torsemide in a sample of form II of torsemide, the inventors have added defined quantities of form I to samples of pure form II and have registered the X-ray diffractograms of the powders as well as the FT-IR spectra in KBr of the mixtures thus obtained.

Example 3a

In this example, there have been added, respectively, 2%, 4% and 8% by weight of form I of torsemide to a sample of pure form II of torsemide. The X-ray diffractogram of the powders of the sample of form II of torsemide contaminated with 2% of form I is represented in FIG. 18.

The measurement conditions of the diffractogram of FIG. 18 are summarised in table 9, whilst the details of the diffractogram of FIG. 18 are reported in table 10: TABLE 9 Sample identification: TORSEMIDE II + I (2%) diffractometer type: PW1710 BASED Tube Anode: Cu Generator tension [kV]: 40 Generator current [mA]: 40 Wavelength alpha1 [Å]: 1.54051 Wavelength alpha2 [Å]: 1.54439 Intensity ratio (alpha2/alpha1): 0.500 Divergence slit: 1° Receiving slit: 0.1 Monochromator used: YES Start angle [°2θ]: 3.000 End angle [°2θ]: 30.000 Step size [°2θ]: 0.010 Maximum intensity: 2460.160 time per step [s]: 0.700 type of scan: STEP Minimum peak tip width: 0.00 Maximum peak tip width: 1.00 Peak base width: 2.00 Minimum significance: 0.75 Number of peaks: 42

TABLE 10 Peak Base Relative Angle Value d Value d Peak width intensity intensity intensity [°2θ] α1 [Å] α2 [Å] [°2θ] [counts] [counts] [%] Significance 5.620 15.7118 15.7513 0.480 12 72 0.5 2.03 6.960 12.6895 12.7215 0.120 48 69 1.9 1.07 7.695 11.4790 11.5079 0.050 64 69 2.6 0.83 9.025 9.7901 9.8148 0.140 1552 69 63.1 4.54 9.260 9.5422 9.5662 0.040 1116 69 45.3 0.81 10.160 8.6989 8.7208 0.120 671 69 27.3 1.99 10.655 8.2958 8.3167 0.050 2460 69 100.0 1.24 11.480 7.7014 7.7208 0.200 219 69 8.9 8.36 11.970 7.3873 7.4059 0.260 234 69 9.5 20.19 13.425 6.5897 6.6063 0.160 132 69 5.4 3.60 14.210 6.2274 6.2431 0.320 28 69 1.1 5.09 14.810 5.9764 5.9915 0.160 24 69 1.0 0.87 15.690 5.6432 5.6574 0.100 543 69 22.1 1.33 15.850 5.5865 5.6006 0.050 676 69 27.5 0.98 16.325 5.4251 5.4387 0.040 433 69 17.6 1.03 16.425 5.3922 5.4058 0.060 292 69 11.9 0.86 17.330 5.1126 5.1255 0.060 213 69 8.7 0.82 18.090 4.8995 4.9119 0.100 400 69 16.3 0.81 18.500 4.7919 4.8039 0.160 918 69 37.3 5.04 18.765 4.7248 4.7367 0.200 1082 69 44.0 17.90 19.280 4.5997 4.6113 0.160 353 69 14.4 2.54 19.880 4.4622 4.4735 0.160 497 69 20.2 1.03 20.320 4.3666 4.3776 0.060 1858 69 75.5 0.87 20.425 4.3444 4.3553 0.040 1648 69 67.0 0.91 20.800 4.2669 4.2776 0.080 420 69 17.1 0.81 21.125 4.2020 4.2126 0.140 458 69 18.6 3.04 21.735 4.0854 4.0957 0.040 458 69 18.6 0.80 22.385 3.9682 3.9782 0.080 767 69 31.2 0.78 22.490 3.9499 3.9599 0.160 1011 69 41.1 10.43 23.030 3.8585 3.8682 0.180 697 69 28.3 6.51 23.420 3.7951 3.8047 0.180 961 69 39.1 11.99 23.895 3.7208 3.7301 0.160 246 69 10.0 0.99 24.490 3.6317 3.6408 0.220 635 69 25.8 17.48 24.950 3.5658 3.5748 0.060 400 69 16.3 0.92 25.525 3.4867 3.4955 0.060 196 69 8.0 0.78 26.050 3.4176 3.4262 0.120 196 69 8.0 1.86 26.935 3.3073 3.3157 0.160 357 69 14.5 5.44 27.610 3.2280 3.2361 0.120 199 69 8.1 0.88 27.960 3.1884 3.1964 0.100 253 69 10.3 1.16 28.430 3.1367 3.1446 0.240 151 59 6.1 4.17 29.015 3.0748 3.0825 0.180 174 69 7.1 4.17 29.690 3.0064 3.0140 0.160 350 69 14.2 4.48

The X-ray diffractogram of the powders of the sample of form II of torsemide contaminated with 4% of form I is represented in FIG. 19.

The measurement conditions of the diffractogram of FIG. 19 are summarised in table 11, whilst the details of the diffractogram of FIG. 19 are reported in table 12: TABLE 11 Sample identification: TORSEMIDE II + I (4%) diffractometer type: PW1710 BASED Tube Anode: Cu Generator tension [kV]: 40 Generator current [mA]: 40 Wavelength alpha1 [Å]: 1.54051 Wavelength alpha2 [Å]: 1.54439 Intensity ratio (alpha2/alpha1): 0.500 Divergence slit: 1° Receiving slit: 0.1 Monochromator used: YES Start angle [°2θ]: 3.000 End angle [°2θ]: 30.000 Step size [°2θ]: 0.010 Maximum intensity: 3422.250 time per step [s]: 0.7000 type of scan: STEP Minimum peak tip width: 0.00 Maximum peak tip width: 1.00 Peak base width: 2.00 Minimum significance: 0.75 Number of peaks: 47

TABLE 12 Peak Base Relative Angle Value d Value d Peak width intensity intensity intensity [°2θ] α1 [Å] α2 [Å] [°2θ] [counts] [counts] [%] Significance 3.320 26.5895 26.6564 0.640 52 69 1.5 2.86 5.595 15.7819 15.8217 0.100 88 69 2.6 1.25 6.860 12.8743 12.9067 0.120 85 69 2.5 2.35 7.595 11.6299 11.6592 0.080 98 69 2.9 0.92 8.805 10.0343 10.0595 0.050 1568 69 45.8 0.91 8.870 9.9609 9.9860 0.030 1789 69 52.3 0.78 9.070 9.7417 9.7662 0.140 2116 69 61.8 30.22 9.970 8.8642 8.8865 0.060 697 69 20.4 1.19 10.475 8.4380 8.4592 0.080 3283 69 95.9 2.71 10.515 8.4060 8.4271 0.080 3422 69 100.0 7.06 11.395 7.7587 7.7782 0.070 292 69 8.5 1.35 11.890 7.4368 7.4555 0.220 296 69 8.6 21.10 12.590 7.0248 7.0425 0.240 24 69 0.7 2.14 13.355 6.6241 6.6408 0.070 219 69 6.4 1.24 14.145 6.2559 6.2716 0.120 44 69 1.3 1.56 14.690 6.0250 6.0402 0.140 41 69 1.2 1.53 15.805 5.6024 5.6165 0.030 681 69 19.9 0.87 16.250 5.4499 5.4636 0.160 543 69 15.9 12.37 17.180 5.1569 5.1699 0.160 400 69 11.7 10.15 18.070 4.9049 4.9173 0.040 586 69 17.1 0.88 18.380 4.8229 4.8350 0.050 1129 69 33.0 1.04 18.440 4.8073 4.8194 0.030 1069 69 31.2 0.97 18.700 4.7411 4.7530 0.050 1498 69 43.8 1.43 19.185 4.6223 4.6339 0.180 433 69 12.6 8.00 19.755 4.4902 4.5015 0.120 484 69 14.1 2.18 20.000 4.4357 4.4469 0.100 835 69 24.4 1.65 20.280 4.3751 4.3861 0.150 2500 69 73.1 34.39 20.705 4.2863 4.2970 0.140 511 69 14.9 6.37 21.095 4.2079 4.2185 0.060 534 69 15.6 1.14 21.630 4.1050 4.1153 0.160 552 69 16.1 11.31 22.040 4.0295 4.0397 0.100 292 69 8.5 1.87 22.400 3.9656 3.9756 0.060 1362 69 39.8 2.35 22.460 3.9551 3.9651 0.060 1082 69 31.6 1.65 22.980 3.8668 3.8765 0.160 841 69 24.6 9.15 23.340 3.8080 3.8176 0.050 1142 69 33.4 1.30 23.775 3.7393 3.7487 0.240 299 69 8.7 3.98 24.420 3.6419 3.6511 0.040 734 69 21.5 1.10 24.865 3.5778 3.5868 0.030 488 69 14.3 0.97 25.365 3.5084 3.5172 0.120 253 69 7.4 1.56 25.990 3.4254 3.4340 0.200 246 69 7.2 7.83 26.845 3.3182 3.3266 0.180 437 69 12.8 10.20 27.540 3.2360 3.2442 0.160 219 69 6.4 1.34 27.890 3.1962 3.2043 0.080 286 69 8.3 0.82 28.375 3.1427 3.1506 0.100 193 69 5.6 1.19 28.950 3.0815 3.0893 0.120 210 69 6.1 2.46 29.580 3.0173 3.0249 0.180 380 69 11.1 6.90 29.695 3.0059 3.0135 0.120 346 69 10.1 2.66

The X-ray diffractogram of the powders of the sample of form II of torsemide contaminated with 8% of form I is represented in FIG. 20. The measurement conditions of the diffractogram of FIG. 20 correspond to these of FIG. 19. In FIG. 20, the signal at approx. 5.7° two theta countersigning the presence of form I of torsemide (8% by weight) in the sample of form II of torsemide is easily detectable.

In particular, from FIGS. 18-20 it appears that whilst a contamination of 4%-8% of form I of torsemide in a sample of form II of torsemide is easily identifiable in the tests by the presence of a signal at 5.7° two theta (a characteristic signature for form I) in the X-ray diffractogram of the powders, instead a contamination of 2% or less is identifiable with difficulty. It is thus concluded that the achievable detection threshold with X-ray diffraction of the powders amounts to 2% (by weight) of form I of torsemide in a sample of pure form II of torsemide. In particular, it is seen that the signal at approx. 5.7° two theta, characteristic of form I of torsemide, is confused with the background noise in the X-ray diffractogram of the powders, if the contamination by form I in a sample of pure form II is less than 2% by weight.

Example 3b FT-IR-Perkin Elmer

In this example, there have been added, respectively 1% and 4% by weight of form I of torsemide to a sample of form II of torsemide obtainable through the method of the present invention. The FT-IR spectrum (Perkin Elmer) of form II of torsemide obtainable through the method of the present invention with the addition of 1% (by weight) of form I of torsemide is represented in FIG. 27. The FT-IR spectrum (Perkin Elmer) of form II of torsemide as obtained through the method of the present invention with the addition of 4% (by weight) of form I of torsemide is represented in FIG. 28. As is apparent from FIGS. 27 and 28 one sees that the achievable detection threshold through evaluation of the FT-IR spectrum in KBr amounts to 1% (by weight) of form I of torsemide in a sample of pure form II of torsemide. In particular, it is seen that the peak at 1697 cm⁻¹, characteristic of form I of torsemide, becomes perceptible at least as a “shoulder” of the adjacent peak in the FT-IR spectrum in KBr, if the contamination by form I in a sample of pure form II is equal to or greater than 1% by weight.

Example 3c FT-IR Jasco

In this example, there have been added, respectively 1%, 3%, 5% and 10% by weight of form I of torsemide to a sample of pure form II of torsemide obtainable through the method of the present invention. The FT-IR spectrum (Jasco) of form II of torsemide as obtainable through the method of the present invention with the addition of 1% (by weight) of form I of torsemide is represented in FIG. 22. The FT-IR spectrum (Jasco) of form II of torsemide as obtainable through the method of the present invention with the addition of 3% (by weight) of form I of torsemide is represented in FIG. 23. The FT-IR spectrum (Jasco) of form II of torsemide as obtainable through the method of the present invention with the addition of 5% (by weight) of form I of torsemide is represented in FIG. 24. The FT-IR spectrum (Jasco) of form II of torsemide as obtainable through the method of the present invention with the addition of 10% (by weight) of form I of torsemide is represented in FIG. 25. A presentation comparing the FT-IR spectra (Jasco) of form II of torsemide as obtainable through the method of the present invention with the addition of 1%, 3%, 5% and 10% (by weight) of form I of torsemide is represented in FIG. 26. As is apparent from FIGS. 22-26 if compared, respectively, to FIGS. 4 and 21 (the later constituting an enlargement), one sees that the achievable detection threshold through the evaluation of the FT-IR spectra in KBr amounts to 1%, and in the best conditions to 0.5% (by weight) of form I of torsemide in a sample of pure form II of torsemide. In particular, it is seen that the peak at approx. 1697 cm⁻¹, characteristic of form I of torsemide, becomes perceptible, at least as a “shoulder” of the adjacent peak in the FT-IR spectrum in KBr, if the contamination by form I in a sample of pure form II is equal to or greater than 1% by weight. One presumes that with the Jasco apparatus, the detectability of form I in form II, in very favourable conditions can be reduced to 0.5%-0.3% by weight.

The measurement conditions of the FT-IR spectrum of the FIGS. 21-26 are summarised in table 13. TABLE 13 Accumulation 32 volts Resolution 4 cm⁻¹ Apodisation Cosine Sample name Torsemide as per the legend to FIG. 21-26 Gain 16 Speed 2.0 mm/sec Delay time 0 sec Light source Ni/Cr Filament Detector 1 Beam splitter KBr

Example 4 Stability Tests of Pure Form II of Torsemide Example 4a Accelerated Test with Pure Solid Form II at 40°±2 C. and 75±5% of Relative Humidity

This type of test which is prescribed according to ICH (Q1A, “Stability testing of new Drug Substances and new Drug Products”, 1^(st) edition Oct. 27, 1997 and 2^(nd) edition Nov. 8, 2000) allows, according to internationally recognised procedures, to extrapolate the results obtained with this accelerated test to a mock storage period at room temperature for over 2 years.

The inventors of the present patent application have subjected a series of pure samples of form II of torsemide to this test, and have assayed with the frequency and to the prescribed terms, the possible polymorphic transformations of the samples through registration of the FT-IR spectra in KBr on a Jasco apparatus. Over 6 months, no detectable polymorphic transformation was witnessed.

Example 4b Prolonged Test with Pure Solid Form II at 25°±2 C. and 60±5% of Relative Humidity

This type of test which is prescribed according to ICH (Q1A, “Stability testing of new Drug Substances and new Drug Products”, 1^(st) edition Oct. 27, 1997 and 2^(nd) edition Nov. 8, 2000) follows possible degradation of the samples under more mild conditions, but over prolonged periods. The inventors of the present patent application have subjected a series of pure samples of form II of torsemide to this test, and have assayed with the frequency and to the prescribed terms, the possible polymorphic transformations of the samples through the registration of the FT-IR spectra in KBr on the Jasco apparatus. After 13 months, one could not see any detectable polymorphic transformation.

Example 4c Drastic Test with Pure Solid Form II at 80° C. for Two Days (Carried Out in the Absence of Light)

In this further test of conformation, it was found that pure and stable form II of torsemide obtainable according to the methods of the present invention does not show a detectable polymorphic transformation if heated at 80° C. for two days. 

1. A solid pharmaceutical formulation comprising pure and stable form II of torsemide.
 2. The pharmaceutical formulation according to claim 1 in which pure and stable form II of torsemide is characterised by the fact of containing less than 1% (by weight) of contamination with form I of torsemide and by the fact of not showing detectable polymorphic transformations in the FT-IR spectrum registered in KBr after 6 months of accelerated stability testing according to ICH (at 40°±2° C./75±5% of relative humidity).
 3. The pharmaceutical formulation according to claim 2 in which pure and stable form II of torsemide is characterised through the following signals in the X-ray diffractogram of the powders expressed in degrees two theta: 9.0±0.1; 9.2±0.1; 10.7±0.1; 15.9±0.1; 18.2±0.1; 18.5±0.1; 18.8±0.1; 20.4±0.1; 22.6±0.1; 23.1±0.1; 23.5±0.1.
 4. The pharmaceutical formulation according to claim 3 in which the pure and stable form II of torsemide is characterised through the signals in the X-ray diffractogram of the powders expressed in degrees two theta as in table
 2. 5. The pharmaceutical formulation according to claim 4 in which the pure and stable form II of torsemide is characterised through the diffractogram of the powders as in FIG.
 3. 6. The pharmaceutical formulation according to claim 2 in which the pure and stable form II of torsemide is characterised through the following peaks in the FT-IR spectrum registered in KBr: 3354±2 cm⁻¹; 3326±2 cm⁻¹; 3085±2 cm⁻¹; 2964±2 cm⁻¹; 1617±2 cm⁻¹; 1555±2 cm⁻¹; 1510±2 cm⁻¹; 1357±2 cm⁻¹; 1326±2 cm⁻¹; 1277±2 cm⁻¹; 1234±2 cm⁻¹; 1151±2 cm⁻¹; 900±2 cm⁻¹; 837±2 cm⁻¹.
 7. The pharmaceutical formulation according to claim 6 in which the pure and stable form II of torsemide is characterised through the peaks in the FT-IR spectrum as in table
 4. 8. The pharmaceutical formulation according to claim 7 in which the pure and stable form II of torsemide is characterised through the FT-IR spectrum as in FIG. 4 or FIG.
 5. 9. The pharmaceutical formulation according to claim 3 in which the pure and stable form II of torsemide is characterised by a melting point in the interval between 159.9° C. and 160.2° C.
 10. The pharmaceutical formulation according to claim 6 in which the pure and stable form II of torsemide is characterised by a melting point in the interval between 159.9° C. and 160.2° C.
 11. The pharmaceutical formulation according to claim 2 in which the pure and stable form II of torsemide is obtainable through a procedure comprising the following steps: suspension of crude dried torsemide in 10 parts of deionised water; the addition of 48% potassium hydrate solution, slowly with stirring maintaining the temperature at 20-25° C., until obtaining complete solution and without exceeding pH 12.5; filtration of the solution thus obtained through 40 micron paper; gradual acidification of the filtrate thus obtained by stirring with 80% acetic acid preferably until reaching a pH of 5.3-5.7 maintaining the temperature at 20-25° C. during the addition, obtaining a suspension; stirring of the suspension for 30 minutes at a temperature of 20-25° C., suction filtration of the solid obtained and washing with water; and drying of the solid in a dryer under vacuum at a temperature of 50° C. 12-16. (canceled) 